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Many chemotherapy agents can induce pulmonary toxicity. Pneumotox.com is a useful internet site that provides a regularly updated list of drugs that have been reported to cause pulmonary toxicity and the patterns of injury inflicted on the respiratory system. These patterns of injury include not only parenchymal lung disease but also pleural manifestations, airway diseases, pulmonary vascular abnormalities, mediastinal changes, and neuromuscular effects.1–3 Pulmonary toxicity is uncommon with most chemotherapy agents and typically consists of parenchymal lung injury (“pneumonitis” or interstitial lung disease). This lung injury can be severe, sometimes resulting in progressive respiratory failure and death, as illustrated by Yoh et al.4 in their study on amrubicin-induced pulmonary toxicity published in this issue of the Journal of Thoracic Oncology.4

As is true with most cases of drug-induced lung disease, the diagnosis of chemotherapy-induced lung disease can be difficult to confirm. The mode of onset (acute or insidious) and timing of clinical manifestations associated with chemotherapy-induced pulmonary toxicity is variable and may present during the initial cycle of treatment, after subsequent cycles, or even years later as is the case with carmustine-associated pulmonary fibrosis.1–3,5 On high-resolution computed tomography, ground-glass opacities, reticular opacities, and/or consolidations are seen in a patchy distribution, usually bilateral. Lung biopsy, whether bronchoscopic or surgical, generally does not yield findings specific for chemotherapy-induced pulmonary toxicity. This is because the histopathologic features seen in these cases are not unique to this form of lung injury and usually consist of various interstitial patterns including nonspecific interstitial pneumonia, organizing pneumonia, diffuse alveolar damage, eosinophilic pneumonia, granulomatous pneumonitis, and pulmonary edema. These histopathologic patterns can be seen in a wide variety of clinical contexts.6 A single chemotherapy agent can be associated with multiple injury patterns.2,3,7,8 In most situations, the clinician relies on the temporal relationship between the administration of chemotherapy and the onset of lung injury along with exclusion of other potential causes, especially infections and metastatic disease, similar to the diagnostic criteria used by Yoh et al.4

Several risk factors that predispose cancer patients to chemotherapy-induced pulmonary toxicity have been described in the literature. These factors include patient's age, smoking history, cumulative dose of the administered drug, renal dysfunction, concomitant chemotherapy or radiation therapy, and oxygen therapy.1,2,9 One particular risk factor of interest in recent years is preexisting interstitial lung disease. In the study by Yoh et al.,4 the incidence of interstitial lung disease was 7% among 100 patients with small cell lung cancer; three patients died of ambirubicin-induced pulmonary toxicity. Among 12 patients with preexisting pulmonary fibrosis (defined by reticular or ground-glass opacities noted on baseline chest radiograph or computed tomography scan), the incidence of ambirubicin-induced pulmonary toxicity was 33%. On multivariate analysis, preexisting pulmonary fibrosis was a significant independent risk factor for the development of ambirubicin-induced pulmonary toxicity. Preexisting interstitial lung disease has also been described to be a risk factor for pulmonary toxicity associated with other chemotherapy agents including methotrexate, everolimus, temsirolimus, oxaliplatin, gefitinib, and erlotinib.2,10–15

Management of chemotherapy-induced pulmonary toxicity usually consists of discontinuing the offending drug and administering corticosteroid therapy either orally or intravenously, partly depending on the severity of pulmonary disease. Although the efficacy of corticosteroid therapy in this clinical setting has not been rigorously tested, available literature and anecdotal experience suggest that it is beneficial in ameliorating chemotherapy-induced pulmonary toxicity.1,2,9 Nonetheless, the beneficial response may be modest or transient and sometimes even ineffective in preventing progressive respiratory insufficiency and death.

Yoh et al.4 suggest avoiding the use of amrubicin in patients with small cell lung cancer who have preexisting pulmonary fibrosis because the risk of pulmonary toxicity is substantial in this subset of patients. Based on their data, this suggestion seems reasonable for the time being. However, it raises questions regarding where the cutoff point should be in diagnosing preexisting “pulmonary fibrosis” based on chest imaging studies because computed tomography findings usually associated with interstitial lung disease can be encountered in asymptomatic individuals, especially the elderly.16 Additional studies in the future will hopefully clarify these issues.

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